title: A hemizygous GYG2 mutation and Leigh syndrome: a possible link?
abstract: Leigh syndrome (LS) is an early-onset progressive neurodegenerative disorder characterized by unique, bilateral neuropathological findings in brainstem, basal ganglia, cerebellum and spinal cord. LS is genetically heterogeneous, with the majority of the causative genes affecting mitochondrial malfunction, and many cases still remain unsolved. Here, we report male sibs affected with LS showing ketonemia, but no marked elevation of lactate and pyruvate. To identify their genetic cause, we performed whole exome sequencing. Candidate variants were narrowed down based on autosomal recessive and X-linked recessive models. Only one hemizygous missense mutation (c.665G>C, p.W222S) in glycogenin-2 (GYG2) (isoform a: NM_001079855) in both affected sibs and a heterozygous change in their mother were identified, being consistent with the X-linked recessive trait. GYG2 encodes glycogenin-2 (GYG2) protein, which plays an important role in the initiation of glycogen synthesis. Based on the structural modeling, the mutation can destabilize the structure and result in protein malfunctioning. Furthermore, in vitro experiments showed mutant GYG2 was unable to undergo the self-glucosylation, which is observed in wild-type GYG2. This is the first report of GYG2 mutation in human, implying a possible link between GYG2 abnormality and LS.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Imagawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.forename: Akio
authors.initials: A
authors.lastname: Yamashita
authors.forename: Masaaki
authors.initials: M
authors.lastname: Shiina
authors.forename: Eihiko
authors.initials: E
authors.lastname: Takahashi
authors.forename: Hideo
authors.initials: H
authors.lastname: Sugie
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogata
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D004252:DNA Mutational Analysis; D059472:Exome; D005964:Glucosyltransferases / Q000737:chemistry / Q000235:genetics*; D006003:Glycogen / Q000378:metabolism*; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics; D057898:Hemizygote; D006801:Humans; D007527:Isoenzymes; D007564:Japan; D007888:Leigh Disease / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D006023:Glycoproteins; D007527:Isoenzymes; C051887:glycogenin; D006003:Glycogen; D005964:Glucosyltransferases; C109150:GYG2 protein, human